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Articles 31 - 46 of 46
Full-Text Articles in Medical Cell Biology
Role For Akt3/Protein Kinase Bγ In Attainment Of Normal Brain Size, Rachel M. Easton, Han Cho, Kristin Roovers, Diana W. Shineman
Role For Akt3/Protein Kinase Bγ In Attainment Of Normal Brain Size, Rachel M. Easton, Han Cho, Kristin Roovers, Diana W. Shineman
Dartmouth Scholarship
Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1−/− mice, which display a …
Multiple Mechanisms Regulate Numa Dynamics At Spindle Poles, Olga Kisurina-Evgenieva, Gary Mack, Quansheng Du, Ian Macara, Alexey Khodjakov, Duane A. Compton
Multiple Mechanisms Regulate Numa Dynamics At Spindle Poles, Olga Kisurina-Evgenieva, Gary Mack, Quansheng Du, Ian Macara, Alexey Khodjakov, Duane A. Compton
Dartmouth Scholarship
The large coiled-coil protein NuMA plays an essential role in organizing microtubule minus ends at spindle poles in vertebrate cells. Here, we use both in vivo and in vitro methods to examine NuMA dynamics at mitotic spindle poles. Using fluorescence recovery after photobleaching, we show that an exogenously expressed green-fluorescent-protein/NuMA fusion undergoes continuous exchange between soluble and spindle-associated pools in living cells. These dynamics require cellular energy and display an average half-time for fluorescence recovery of approximately 3 minutes. To explore how NuMA dynamics at spindle poles is regulated, we exploited the association of NuMA with microtubule asters formed in …
Fibroblast Growth Factor 2 Endocytosis In Endothelial Cells Proceed Via Syndecan-4-Dependent Activation Of Rac1 And A Cdc42-Dependent Macropinocytic Pathway, Eugene Tkachenko, Esther Lutgens, Radu-Virgil Stan, Michael Simons
Fibroblast Growth Factor 2 Endocytosis In Endothelial Cells Proceed Via Syndecan-4-Dependent Activation Of Rac1 And A Cdc42-Dependent Macropinocytic Pathway, Eugene Tkachenko, Esther Lutgens, Radu-Virgil Stan, Michael Simons
Dartmouth Scholarship
Full activity of fibroblast growth factors (FGFs) requires their internalization in addition to the interaction with cell surface receptors. Recent studies have suggested that the transmembrane proteoglycan syndecan-4 functions as a FGF2 receptor. In this study we investigated the molecular basis of syndecan endocytosis and its role in FGF2 internalization in endothelial cells. We found that syndecan-4 uptake, induced either by treatment with FGF2 or by antibody clustering, requires the integrity of plasma membrane lipid rafts for its initiation, occurs in a non-clathrin-, non-dynamin-dependent manner and involves Rac1, which is activated by syndecan-4 clustering. FGF2 was internalized in a complex …
Coupling Of Termination, 3′ Processing, And Mrna Export, C. M. Hammell, Stefan Gross, Daniel Zenklusen, Catherine V. Heath, Francoise Stutz, Claire Moore, C. N. Cole
Coupling Of Termination, 3′ Processing, And Mrna Export, C. M. Hammell, Stefan Gross, Daniel Zenklusen, Catherine V. Heath, Francoise Stutz, Claire Moore, C. N. Cole
Dartmouth Scholarship
In a screen to identify genes required for mRNA export in Saccharomyces cerevisiae, we isolated an allele of poly(A) polymerase (PAP1) and novel alleles encoding several other 3′ processing factors. Many newly isolated and some previously described mutants (rna14-48, rna14-49, rna14-64, rna15-58, and pcf11-1 strains) are defective in polymerase II (Pol II) termination but, interestingly, retain the ability to polyadenylate these improperly processed transcripts at the nonpermissive temperature. Deletion of the cis-acting sequences required to couple 3′ processing and termination also …
Remodeling Of Organelle-Bound Actin Is Required For Yeast Vacuole Fusion, Gary Eitzen, Li Wang, Naomi Thorngren, William Wickner
Remodeling Of Organelle-Bound Actin Is Required For Yeast Vacuole Fusion, Gary Eitzen, Li Wang, Naomi Thorngren, William Wickner
Dartmouth Scholarship
Actin participates in several intracellular trafficking pathways. We now find that actin, bound to the surface of purified yeast vacuoles in the absence of cytosol or cytoskeleton, regulates the last compartment mixing stage of homotypic vacuole fusion. The Cdc42p GTPase is known to be required for vacuole fusion. We now show that proteins of the Cdc42p-regulated actin remodeling cascade (Cdc42p --> Cla4p --> Las17p/Vrp1p --> Arp2/3 complex --> actin) are enriched on isolated vacuoles. Vacuole fusion is dramatically altered by perturbation of the vacuole-bound actin, either by mutation of the ACT1 gene, addition of specific actin ligands such as latrunculin …
Fibroblast Growth Factor–Specific Modulation Of Cellular Response By Syndecan-4, Arie Horowitz, Eugene Tkachenko, Michael Simons
Fibroblast Growth Factor–Specific Modulation Of Cellular Response By Syndecan-4, Arie Horowitz, Eugene Tkachenko, Michael Simons
Dartmouth Scholarship
Proteoglycans participate in growth factor interaction with the cell surface through their heparan sulfate chains (HS), but it is not known if they are otherwise involved in growth factor signaling. It appears now that the syndecan-4 core protein, a transmembrane proteoglycan shown previously to bind phosphatidylinositol 4,5-bisphosphate (PIP(2)) and activate PKC alpha, participates in mediating the effects of fibroblast growth factor (FGF)2 on cell function. Mutations in the cytoplasmic tail of syndecan-4 that either reduced its affinity to PIP(2) (PIP(2)(-)) or disrupted its postsynaptic density 95, disk large, zona occludens-1 (PDZ)-dependent binding (PDZ(-)) produced a FGF2-specific dominant negative phenotype in …
Transcriptional Interference By Independently Regulated Genes Occurs In Any Relative Arrangement Of The Genes And Is Influenced By Chromosomal Integration Position, Susan K. Eszterhas, Eric E. Bouhassira, David I. K. Martin, Steven Fiering
Transcriptional Interference By Independently Regulated Genes Occurs In Any Relative Arrangement Of The Genes And Is Influenced By Chromosomal Integration Position, Susan K. Eszterhas, Eric E. Bouhassira, David I. K. Martin, Steven Fiering
Dartmouth Scholarship
Transcriptional interference is the influence, generally suppressive, of one active transcriptional unit on another unit linked in cis. Its wide occurrence in experimental systems suggests that it may also influence transcription in many loci, but little is known about its precise nature or underlying mechanisms. Here we report a study of the interaction of two nearly identical transcription units juxtaposed in various arrangements. Each reporter gene in the constructs has its own promoter and enhancer and a strong polyadenylation signal. We used recombinase-mediated cassette exchange (RMCE) to insert the constructs into previously tagged genomic sites in cultured cells. This …
Three V-Snares And Two T-Snares, Present In A Pentameric Cis-Snare Complex On Isolated Vacuoles, Are Essential For Homotypic Fusion, Christian Ungermann, Gabriele F. Von Mollard, Ole N. Jensen, Nathan Margolis, Tom H. Stevens, William Wickner
Three V-Snares And Two T-Snares, Present In A Pentameric Cis-Snare Complex On Isolated Vacuoles, Are Essential For Homotypic Fusion, Christian Ungermann, Gabriele F. Von Mollard, Ole N. Jensen, Nathan Margolis, Tom H. Stevens, William Wickner
Dartmouth Scholarship
Vacuole SNAREs, including the t-SNAREs Vam3p and Vam7p and the v-SNARE Nyv1p, are found in a multisubunit "cis" complex on isolated organelles. We now identify the v-SNAREs Vti1p and Ykt6p by mass spectrometry as additional components of the immunoisolated vacuolar SNARE complex. Immunodepletion of detergent extracts with anti-Vti1p removes all the Ykt6p that is in a complex with Vam3p, immunodepletion with anti-Ykt6p removes all the Vti1p that is complexed with Vam3p, and immunodepletion with anti-Nyv1p removes all the Ykt6p in complex with other SNAREs, demonstrating that they are all together in the same cis multi-SNARE complex. After priming, which disassembles …
The Gtp-Bound Form Of The Yeast Ran/Tc4 Homologue Blocks Nuclear Protein Import And Appearance Of Poly(A)+ Rna In The Cytoplasm., Gabriel Schlenstedt, Claudio Saavedra, Jonathan D. Loeb, Charles N. Cole, Pamela A. Silver
The Gtp-Bound Form Of The Yeast Ran/Tc4 Homologue Blocks Nuclear Protein Import And Appearance Of Poly(A)+ Rna In The Cytoplasm., Gabriel Schlenstedt, Claudio Saavedra, Jonathan D. Loeb, Charles N. Cole, Pamela A. Silver
Dartmouth Scholarship
Ran/TC4, a Ras-like GTP-binding protein, and its nucleotide exchanger, RCC1, have been implicated in control of protein movement into the nucleus and cytoplasmic accumulation of mRNA. Saccharomyces cerevisiae contains two homologues of the mammalian Ran/TC4, encoded by the GSP1 and GSP2 genes. We have constructed yeast strains that overproduce either wild-type Gsp1 or a form of Gsp1 with glycine-21 converted to valine (Gsp1-G21V), which we show stabilizes the GTP-bound form. Cells producing Gsp1-G21V have defects in localization of nuclear proteins; nuclear proteins accumulate in the cytoplasm following galactose induction of Gsp1-G21V. Similarly, cells producing Gsp1-G21V retain poly(A)+ RNA in their …
Indistinguishable Nuclear Factor Binding To Functional Core Sites Of The T-Cell Receptor Delta And Murine Leukemia Virus Enhancers., Juan M. Redondo, Jeffrey L. Pfohl, Cristina Hernandez-Munain, Shuwen Wang, Nancy A. Speck, Michael S. Krangel
Indistinguishable Nuclear Factor Binding To Functional Core Sites Of The T-Cell Receptor Delta And Murine Leukemia Virus Enhancers., Juan M. Redondo, Jeffrey L. Pfohl, Cristina Hernandez-Munain, Shuwen Wang, Nancy A. Speck, Michael S. Krangel
Dartmouth Scholarship
We have previously shown that the delta E3 site is an essential element for transcriptional activation by the human T-cell receptor (TCR) delta enhancer and identified two factors, NF-delta E3A and NF-delta E3C, that bound to overlapping core (TGTGGTTT) and E-box motifs within delta E3. In this study, we show that protein binding to the core motif is necessary but not sufficient for transcriptional activation by the delta E3 element. In contrast, protein binding to the E-box motif does not contribute significantly to enhancer activity. A similar core motif present within the enhancers of T-cell-tropic murine retroviruses has been shown …
Insulin Receptor And Epidermal Growth Factor Receptor Dephosphorylation By Three Major Rat Liver Protein-Tyrosine Phosphatases Expressed In A Recombinant Bacterial System, Naotake Hashimoto, Wei-Ren Zhang, Barry J. Goldstein
Insulin Receptor And Epidermal Growth Factor Receptor Dephosphorylation By Three Major Rat Liver Protein-Tyrosine Phosphatases Expressed In A Recombinant Bacterial System, Naotake Hashimoto, Wei-Ren Zhang, Barry J. Goldstein
Department of Medicine Faculty Papers
Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of signal transduction mediated by reversible protein-tyrosine phosphorylation. In order to characterize individual rat hepatic PTPases that might have specificity for autophosphorylated receptor tyrosine kinases, we isolated cDNA segments encoding three PTPases (PTPase 1B, LAR and LRP) that are expressed in insulin-sensitive liver and skeletal muscle tissue, and evaluated their catalytic activity in vitro. The intrinsic PTPase activities of the full-length PTPase 1B protein and the cytoplasmic domains of LAR and LRP were studied by expression of recombinant cDNA constructs in the inducible bacterial vector pKK233-2 using extracts of …
Purification Of Core-Binding Factor, A Protein That Binds The Conserved Core Site In Murine Leukemia Virus Enhancers., Shuwen W. Wang, Nancy A. Speck
Purification Of Core-Binding Factor, A Protein That Binds The Conserved Core Site In Murine Leukemia Virus Enhancers., Shuwen W. Wang, Nancy A. Speck
Dartmouth Scholarship
The Moloney murine leukemia virus causes thymic leukemias when injected into newborn mice. A major genetic determinant of the thymic disease specificity of the Moloney virus genetically maps to two protein binding sites in the Moloney virus enhancer, the leukemia virus factor b site and the adjacent core site. Point mutations introduced into either of these sites significantly shifts the disease specificity of the Moloney virus from thymic leukemia to erythroleukemia (N. A. Speck, B. Renjifo, E. Golemis, T. Frederickson, J. Hartley, and N. Hopkins, Genes Dev. 4:233-242, 1990). We have purified several polypeptides that bind to the core site …
Interleukin-2-Triggered Raf-1 Expression, Phosphorylation, And Associated Kinase Activity Increase Through G1 And S In Cd3-Stimulated Primary Human T Cells., Antanina Zmuidzinas, Harvey J. Mamon, Thomas M. Roberts, Kendall A. Smith
Interleukin-2-Triggered Raf-1 Expression, Phosphorylation, And Associated Kinase Activity Increase Through G1 And S In Cd3-Stimulated Primary Human T Cells., Antanina Zmuidzinas, Harvey J. Mamon, Thomas M. Roberts, Kendall A. Smith
Dartmouth Scholarship
To gain further insight into the role of Raf-1 in normal cell growth, c-raf-1 mRNA expression, Raf-1 protein production, and Raf-1-associated kinase activity in normal human T cells were analyzed. In contrast to the constitutive expression of Raf-1 in continuously proliferating cell lines, c-raf-1 mRNA and Raf-1 protein levels were barely detectable in freshly isolated G0 T lymphocytes. Previous work with fibroblasts has suggested that Raf-1 plays a signaling role in the G0-G1 phase transition. In T cells, triggering via the T-cell antigen receptor (TCR)-CD3 complex (TCR/CD3) resulted in an approximately fourfold increase in c-raf-1 mRNA. In addition, the promotion …
Fine-Structure Analysis Of The Processing And Polyadenylation Region Of The Herpes Simplex Virus Type 1 Thymidine Kinase Gene By Using Linker Scanning, Internal Deletion, And Insertion Mutations., Fang Zhang, Roger M. Denome, Charles N. Cole
Fine-Structure Analysis Of The Processing And Polyadenylation Region Of The Herpes Simplex Virus Type 1 Thymidine Kinase Gene By Using Linker Scanning, Internal Deletion, And Insertion Mutations., Fang Zhang, Roger M. Denome, Charles N. Cole
Dartmouth Scholarship
Most eucaryotic mRNAs are polyadenylated. In higher eucaryotes, the sequence AATAAA is located 7 to 30 base pairs (bp) upstream from the site of processing and polyadenylation and is a critical part of the signal for processing and polyadenylation. Efficient cleavage and polyadenylation also require sequences downstream of polyadenylation sites. The herpes simplex virus type 1 thymidine kinase (tk) gene contains two copies of the AATAAA hexanucleotide and a GT box (18 of 19 consecutive residues are G or T) previously shown to be required for efficient processing and polyadenylation of tk mRNA (C. N. Cole and T. P. Stacy, …
Absence Of A Structural Basis For Intracellular Recognition And Differential Localization Of Nuclear And Plasma Membrane-Associated Forms Of Simian Virus 40 Large Tumor Antigen., Donald L. Jarvis, Charles N. Cole, Janet S. Butel
Absence Of A Structural Basis For Intracellular Recognition And Differential Localization Of Nuclear And Plasma Membrane-Associated Forms Of Simian Virus 40 Large Tumor Antigen., Donald L. Jarvis, Charles N. Cole, Janet S. Butel
Dartmouth Scholarship
The simian virus 40 large tumor antigen (T-ag) is found in both the nuclei (nT-ag) and plasma membranes (mT-ag) of simian virus 40-infected or -transformed cells. It is not known how newly synthesized T-ag molecules are recognized, sorted, and transported to their ultimate subcellular destinations. One possibility is that these events depend upon structural differences between nT-ag and mT-ag. To test this possibility, we compared the structures of nT-ag and mT-ag from simian virus 40-infected cells. No differences between the two forms of T-ag were detected by migration in polyacrylamide gels, by Staphylococcus aureus V8 partial proteolytic mapping of methionine- …
Identification Of Sequences In The Herpes Simplex Virus Thymidine Kinase Gene Required For Efficient Processing And Polyadenylation., Charles N. Cole, Terryl P. Stacy
Identification Of Sequences In The Herpes Simplex Virus Thymidine Kinase Gene Required For Efficient Processing And Polyadenylation., Charles N. Cole, Terryl P. Stacy
Dartmouth Scholarship
The herpes simplex virus (HSV) type 1 thymidine kinase gene (tk) was resected from its 3' end with BAL 31 exonuclease. Two sets of plasmids were isolated that lacked information distal to the two copies of the hexanucleotide 5'-AATAAA-3' located at the 3' end of the HSV tk gene. The presence of a simian virus 40 origin of DNA replication in each plasmid facilitated analysis of patterns of transcription in transfected Cos-1 monkey cells. Transcription analyses were performed with an S1 nuclease protection assay. Efficient processing and polyadenylation at the normal site still occurred when all sequences more than 44 …